Delivery of ibuprofen and other compounds

ABSTRACT

The present invention generally relates to the transdermal delivery of various compositions. In some aspects, the transdermal delivery may be facilitated by the use of a hostile biophysical environment. One set of embodiments provides a composition for topical delivery comprising ibuprofen and/or an ibuprofen salt, a nitric oxide donor, and optionally, a hostile biophysical environment. In some cases, the composition may be stabilized using a stabilization polymer such as xanthan gum, KELTROL® BT and/or KELTROL® RD; propylene glycol; and a polysorbate surfactant such as Polysorbate 20, which unexpectedly provides temperature stability to the composition, e.g., at elevated temperatures such as at least 40° C. (at least about 104° F.), as compared to compositions lacking one or more of these.

FIELD OF INVENTION

The present invention generally relates to the transdermal delivery ofcompositions.

BACKGROUND

Local transdermal delivery of drugs, while desirable, is limited bycurrent technologies. Few pharmaceutical entities have successfully beendelivered transdermally in effective dosages. For example, a limitednumber of drugs, such as steroids, nicotine, and nitroglycerine, whichare non-charged and do not form hydrogen bonds, have been successfullydelivered by passive diffusion, relying on the concentration gradientbetween outside and inside the skin to deliver the drug in accordancewith Fick's first law of diffusion. The amount of pharmaceutical agentthat can be delivered through simple diffusion is also limited. Forinstance, once the concentration inside the stratum corneum becomesequal to that outside, flow of pharmaceutical agent may stop. Thus,improvements in the transdermal delivery of compositions, locally orsystemically, are needed.

SUMMARY OF THE INVENTION

The present invention generally relates to the transdermal delivery ofcompositions, locally or systemically, and in some embodiments, to thetransdermal delivery of compositions by a hostile biophysicalenvironment. Examples include ibuprofen or other pharmaceutical agents.The subject matter of the present invention involves, in some cases,interrelated products, alternative solutions to a particular problem,and/or a plurality of different uses of one or more systems and/orarticles.

In one set of embodiments, compositions having relatively hightemperature stability are provided. In some embodiments, for instance, acomposition of the present invention may include a stabilizationpolymer, propylene glycol, and a polysorbate surfactant. Non-limitingexamples of stabilization polymers include xanthan gum, KELTROL® BTand/or KELTROL® RD; an example of a polysorbate surfactant isPolysorbate 20. Such a combination of components to create hightemperature stability are surprising, since compositions involving anytwo of these components (but not the third) were found to lack such hightemperature stabilization properties. It is not currently known why thiscombination of components is remarkably effective at facilitatingrelatively high temperature stability of the compositions discussedherein, as these components are not known to participate in anysignificant chemical reactions with each other, and high temperaturestability is greatly reduced when one of the components is removed. Inaddition, propylene glycol is not known to work in pharmaceuticalcompositions as a stabilizing agent.

Thus, in one aspect, the present invention is directed to a compositionfor topical delivery to the skin of a subject. In one set ofembodiments, the composition includes a nitric oxide donor, a hostilebiophysical environment, a stabilization polymer, propylene glycol, apolysorbate surfactant, and ibuprofen and/or a ibuprofen salt.

In another set of embodiments, at least about 80% by weight of thecomposition comprises water, at least one chloride salt, a nitric oxidedonor, a stabilization polymer, propylene glycol, a polysorbatesurfactant, and ibuprofen and/or a ibuprofen salt.

The composition, in yet another set of embodiments, includes water,sodium chloride, a nitric oxide donor, glyceryl stearate, cetyl alcohol,potassium chloride, squalane, a stabilization polymer, isopropylmyristate, oleic acid, propylene glycol, a polysorbate surfactant, andibuprofen and/or a ibuprofen salt.

The composition, in still another set of embodiments, includes each ofthe following compounds at concentrations of no more than ±20% of thestated concentrations: water at a concentration of about 44.2% weight,sodium chloride at a concentration of about 10% weight, a nitric oxidedonor at a concentration of about 7.5% weight, glyceryl stearate at aconcentration of about 7% weight, cetyl alcohol at a concentration ofabout 7% weight, potassium chloride at a concentration of about 5.5%weight, propylene glycol at a concentration of about 5% weight, squalaneat a concentration of about 4% weight, a polysorbate surfactant at aconcentration of about 2% by weight, and isopropyl myristate at aconcentration of about 1% weight, oleic acid at a concentration of about1% weight, a stabilization polymer at a concentration of about 0.8%weight, ibuprofen and/or a ibuprofen salt at a concentration of about5.0% weight.

The composition, in another set of embodiments, includes a nitric oxidedonor, a hostile biophysical environment, a stabilization polymer,propylene glycol, a polysorbate surfactant and ibuprofen and/or aibuprofen salt. In still another set of embodiments, the compositionincludes a stabilization polymer, propylene glycol, a polysorbatesurfactant, and ibuprofen and/or a ibuprofen salt. In another set ofembodiments, at least about 80% by weight of the composition compriseswater, at least one chloride salt, a stabilization polymer, propyleneglycol, a polysorbate surfactant, and ibuprofen and/or a ibuprofen salt.

In another aspect, the present invention is directed to the use of acomposition in the preparation of a medicament for treatment of adisease or condition as discussed herein. In one set of embodiments, thecomposition for the medicament comprises a nitric oxide donor, a hostilebiophysical environment, a stabilization polymer, propylene glycol, apolysorbate surfactant, and ibuprofen and/or a ibuprofen salt.

In another set of embodiments, at least about 80% by weight of thecomposition for the medicament comprises water, at least one chloridesalt, a nitric oxide donor, a stabilization polymer, propylene glycol, apolysorbate surfactant, and ibuprofen and/or a ibuprofen salt.

The composition for the medicament, in yet another set of embodiments,includes water, sodium chloride, a nitric oxide donor, glycerylstearate, cetyl alcohol, potassium chloride, squalane, a stabilizationpolymer, isopropyl myristate, oleic acid, propylene glycol, apolysorbate surfactant, and ibuprofen and/or a ibuprofen salt.

The composition for the medicament, in still another set of embodiments,includes each of the following compounds at concentrations of no morethan ±20% of the stated concentrations: water at a concentration ofabout 44.2% weight, sodium chloride at a concentration of about 10%weight, a nitric oxide donor at a concentration of about 7.5% weight,glyceryl stearate at a concentration of about 7% weight, cetyl alcoholat a concentration of about 7% weight, potassium chloride at aconcentration of about 5.5% weight, propylene glycol at a concentrationof about 5% weight, squalane at a concentration of about 4% weight, apolysorbate surfactant at a concentration of about 2% by weight, andisopropyl myristate at a concentration of about 1% weight, oleic acid ata concentration of about 1% weight, a stabilization polymer at aconcentration of about 0.8% weight, ibuprofen and/or a ibuprofen salt ata concentration of about 5.0% weight.

The composition for the medicament, in another set of embodiments,includes a nitric oxide donor, a hostile biophysical environment, astabilization polymer, propylene glycol, a polysorbate surfactant andibuprofen and/or a ibuprofen salt. In still another set of embodiments,the composition for the medicament includes a stabilization polymer,propylene glycol, a polysorbate surfactant, and ibuprofen and/or aibuprofen salt. In another set of embodiments, at least about 80% byweight of the composition for the medicament comprises water, at leastone chloride salt, a stabilization polymer, propylene glycol, apolysorbate surfactant, and ibuprofen and/or a ibuprofen salt.

The present invention, in another aspect, is directed to a method ofmaking one or more of the embodiments described herein. In yet anotheraspect, the present invention is directed to a method of using one ormore of the embodiments described herein. In still another aspect, thepresent invention is directed to a method of promoting one or more ofthe embodiments described herein.

Other advantages and novel features of the present invention will becomeapparent from the following detailed description of various non-limitingembodiments of the invention. In cases where the present specificationand a document incorporated by reference include conflicting and/orinconsistent disclosure, the present specification shall control. If twoor more documents incorporated by reference include conflicting and/orinconsistent disclosure with respect to each other, then the documenthaving the later effective date shall control.

DETAILED DESCRIPTION

The present invention generally relates to the transdermal delivery ofvarious compositions. In some aspects, transdermal delivery may befacilitated by the use of a hostile biophysical environment. One set ofembodiments provides a composition for topical delivery comprisingibuprofen and/or an ibuprofen salt, and optionally, a hostilebiophysical environment and/or a nitric oxide donor. In some cases, thecomposition may be stabilized using a combination of a stabilizationpolymer (such as xanthan gum, KELTROL® BT and/or KELTROL® RD), propyleneglycol, and a polysorbate surfactant such as Polysorbate 20, whichcombination unexpectedly provides temperature stability to thecomposition, e.g., at elevated temperatures such as at least 40° C. (atleast about 104° F.), as compared to compositions lacking one or more ofthese.

One aspect of the invention provides compositions for the topicaldelivery of substances such as pharmaceutical agents (e.g., drugs,biological compounds, etc.). The pharmaceutical agents may be applied tothe skin of a subject, e.g. a human, to aid in treatment of medicalconditions or diseases, and/or the symptoms associated thereof. In someembodiments, the invention provides for the treatment of medicalconditions or diseases and/or ailments using pharmaceutical agents (forexample, to treat a subject diagnosed with a medical condition ordisease, as described herein), and in some cases, the invention providesfor the delivery of a minimum amount of pharmaceutical agents to provideeffective levels of medication to an effected area topically whilelimiting side effects. In some cases, the effective dosage of thepharmaceutical agent may be lower than the effective dosage of thepharmaceutical agent when taken orally.

For example, in one set of embodiments, the pharmaceutical agent isibuprofen and/or an ibuprofen salt. While ibuprofen is an effectiveagent against pain when orally administered, it can be irritating to thelining of the stomach, and people with a tendency to develop ulcers orhave an irritated upper gastrointestinal track are typically warned toavoid the use of ibuprofen. The present invention thus allows, in oneset of embodiments, the topical application of ibuprofen to a site ofinflammation or pain, while avoiding the rest of the body, especiallythe stomach. The composition may also include a nitric oxide donor suchas L-arginine, which may be useful, for example, to increase localizedblood flow at the site of delivery, which in turn can enhance deliveryof the pharmaceutical agent, e.g., locally or systemically. In somecases, the enhancement may occur by maintaining an appropriateconcentration gradient at the site of delivery.

In addition, in some cases, the composition may be formulated such thatit creates a hostile biophysical environment to a pharmaceutical agent(e.g., to ibuprofen). In a hostile biophysical environment, theenvironment surrounding the pharmaceutical agent may be such that thepharmaceutical agent is in a chemically and/or energetically unfavorableenvironment, relative to the skin (e.g., the chemical potential and/orthe free energy of the pharmaceutical agent within the hostilebiophysical environment is significantly greater than the chemicalpotential and/or the free energy of the pharmaceutical agent within theskin, thus energetically favoring transport into the skin), especiallythe stratum corneum.

Examples of such compositions are discussed in International PatentApplication No. PCT/US2005/013228, filed Apr. 19, 2005, entitled“Transdermal Delivery of Beneficial Substances Effected by a HostileBiophysical Environment,” by E. Fossel, published as WO 2005/102282 onNov. 3, 2005, incorporated herein by reference. Other techniques forhostile biophysical environments are discussed in detail herein.However, such compositions often are not stable at relatively hightemperatures, e.g., at elevated temperatures such as at least 40° C. (atleast about 104° F.) for periods of time of at least about a day. Thus,in one set of embodiments, compositions having relatively hightemperature stability are provided herein. In some embodiments, forinstance, a composition of the present invention may further include astabilization polymer, propylene glycol, and a polysorbate surfactant.Non-limiting examples of stabilization polymers include xanthan gum,KELTROL® BT and/or KELTROL® RD; an example of a polysorbate surfactantis Polysorbate 20. Additional examples are discussed herein.

Such a combination of components to create high temperature stabilityare surprising, since compositions involving any two of these components(but not the third) were found to lack such high temperaturestabilization properties. It is not currently known why this combinationof components is remarkably effective at facilitating relatively hightemperature stability of the compositions discussed herein, as thesecomponents are not known to participate in any significant chemicalreactions with each other, and high temperature stability is greatlyreduced when one of the components is removed. In addition, propyleneglycol is not known to work in pharmaceutical compositions as astabilizing agent.

For instance, in one set of embodiments, a composition may be determinedto be one that has high temperature stability by determining whether thecomposition exhibits phase separation over a relatively long period oftime, e.g., over at least an hour, at least about 2 hours, at least aday, at least about a week, at least about 4 weeks, etc. For example, insome embodiments, a composition is exposed to ambient temperature andpressure for at least 1 hour, and the composition is then analyzed todetermine whether the composition exhibits phase separation or a changein phase. A stable compound is one that exhibits no phase separation,whereas an unstable compound may exhibit phase separation. Suchstability may be useful, for example, for storage of the composition,transport of the composition, shelf life, or the like.

The pharmaceutical agent (e.g., ibuprofen and/or an ibuprofen salt) maybe present at any suitable concentration. For instance, in some cases,the pharmaceutical agent may be present at a concentration of at leastabout 1%, at least about 2%, at least about 3%, at least about 4%, atleast about 5%, at least about 6%, at least about 7%, at least about7.5%, at least about 8%, at least about 9%, or at least about 10% byweight of the composition. In addition, the pharmaceutical agent may bepresent in native form and/or as a salt. For example, if ibuprofen ispresent, it may be used in its native form, and/or as one or moreibuprofen salts, e.g., the sodium salt of ibuprofen, the potassium saltof ibuprofen, the lysine salt of ibuprofen, the arginine salt ofibuprofen, etc. Ibuprofen is readily commercially available.

As used herein, a “stabilization polymer” is a polymer that comprisesxanthan gum, a xanthan gum derivative, and/or a xanthan gum equivalent,for example, KELTROL® BT and/or KELTROL® RD, KELZAN® XC, KELZAN® XCD,KELZAN® D, KELZAN® CC, XANTURAL® 180, XANTURAL® 75, or the like, all ofwhich can be obtained commercially from various suppliers. In someembodiments, combinations of these and/or other polymers are alsopossible. In some cases, the stabilization polymer is chosen to be onewhich is at least generally regarded as safe for use in humans. Inaddition, in certain embodiments, the stabilization polymer is producedsynthetically, and/or one which has been purified to some degree. Thestabilization polymer may have any suitable molecular weight, forexample, at least about 1 million, at least about 2 million, at leastabout 5 million, at least about 10 million, at least about 25 million,or at least about 50 million.

The stabilization polymer may be present at any suitable concentrationwithin the composition. For example, the stabilization polymer may bepresent at a concentration of at least about 0.1%, at least about 0.2%,at least about 0.3%, at least about 0.4%, at least about 0.5%, at leastabout 0.6%, at least about 0.7%, at least about 0.8%, at least about0.9%, or at least about 1% by weight of the composition. In some cases,more than one stabilization polymer may be present, and eachstabilization polymer may be present in any suitable amount. As aspecific example, in certain embodiments, the stabilization polymerconsists essentially of KELTROL® BT and/or KELTROL® RD. In certaininstances, the stabilization polymer may have a fixed ratio of KELTROL®BT and/or KELTROL® RD, for example, 1:1 or 3:5 by weight. In anotherexample, the KELTROL® BT may be present at a concentration of about 0.3%by weight and the KELTROL® RD may be present at a concentration of 0.5%by weight of the composition, or one or both of these may be present atone of the other concentrations described above. Combinations of theseand/or other stabilization polymers are also contemplated in otherembodiments, e.g., KELTROL® BT and xanthan gum, KELTROL® RD and xanthangum, etc. In some cases, thickening agents can be used instead of, or inconjunction with a stabilization polymer. Many thickening agents can beobtained commercially. Thickening agents include those used in the foodindustry, or are GRAS agents (generally regarded as safe), e.g.,alginin, guar gum, locust bean gum, collagen, egg white, furcellaran,gelatin, agar, and/or carrageenan, as well as combinations of theseand/or other stabilization polymers. It should thus be appreciated that,in the specification herein, references to stabilization polymers, inother embodiments, should be understood to also include thickeningagents in conjunction or instead of stabilization polymers,

Propylene glycol can be obtained commercially, and can be present as anystereoisomer or racemic mixture of isomers. It may also be present atany suitable concentration. For instance, propylene glycol may bepresent at a concentration of at least about 1%, at least about 2%, atleast about 3%, at least about 4%, at least about 5%, at least about 6%,at least about 7%, at least about 8%, at least about 9%, or at leastabout 10% by weight of the composition. In some cases, other glycols canbe used in conjunction or instead of propylene glycol, such as butyleneglycol. Accordingly, it should thus be appreciated that, in thespecification herein, references to propylene glycol, in otherembodiments, should be understood to also include other glycols inconjunction or instead of propylene glycol.

In addition, a polysorbate surfactant can also be present any suitableconcentration within the composition. For instance, in some cases, thepolysorbate surfactant may be present at a concentration of at leastabout 1%, at least about 2%, at least about 3%, at least about 4%, atleast about 5%, at least about 6%, at least about 7%, at least about 8%,at least about 9%, or at least about 10% by weight of the composition. A“polysorbate surfactant,” as used herein, is a surfactant comprising apolysorbate. For example, the surfactant may comprise sorbitanmonolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitanmonooleate, or another sorbitan salt. In some cases, the polysorbatesurfactant has a molecular formula:

where w, x, y, and z are any suitable positive integers. w, x, y, and zmay also each be independently the same or different. In one set ofembodiments, w+x+y+z is 20 (e.g., as in Polysorbate 20). In some cases,other polymeric sugars can be used instead of, or in conjunction with, apolysorbate surfactant. Thus, it should be appreciated that, in thespecification herein, references to a polysorbate surfactant are by wayof example, and in other embodiments, it should be understood thatreferences to a polysorbate surfactant may include other polymericsugars in conjunction or instead of a polysorbate surfactant.

In some cases, the composition may have a fixed ratio of thestabilization polymer to propylene glycol to the polysorbate surfactant.For instance, the ratio of these may be about 1:1:1, about 1:6:3, about1:6:2, about 1:7:2, about 1:7:3, about 1.5:1:1, about 1.5:6:3, about1.5:6:4, about 1:6:2.5, about 1:6.25:2.5, about 1:6.25:2.5, etc. Asmentioned above, such ratios may be useful, in certain embodiments ofthe invention, in providing temperature stability to the composition.

As discussed, the composition may also comprise a nitric oxide donor,for example, L-arginine and/or L-arginine hydrochloride. In some cases,such a nitric oxide donor may be used to increase localized blood flowat the site where the composition is applied, which may enhance deliveryof the pharmaceutical agent. The nitric oxide donor may be present atany suitable concentration within the composition. For instance, in somecases, the nitric oxide donor is present at a concentration of at leastabout 1%, at least about 2%, at least about 3%, at least about 4%, atleast about 5%, at least about 6%, at least about 7%, at least about7.5%, at least about 8%, at least about 9%, or at least about 10% byweight of the composition. In some cases, one or more nitric oxidedonors (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, etc. nitric oxide donors) maybe used.

A “nitric oxide donor,” as used herein, is a compound that is able torelease nitric oxide and/or chemically transfer the nitric oxide moietyto another molecule, directly or indirectly, for example, through abiological process. The nitric oxide donor may release nitric oxide intothe skin, and/or tissues such as muscles and/or elements of thecirculatory system in close proximity to the surface of the skin.Non-limiting examples of nitric oxide donors include arginine (e.g.,L-arginine and/or D-arginine), arginine derivatives (e.g., L-argininehydrochloride and/or D-arginine hydrochloride), nitroglycerin,polysaccharide-bound nitric oxide-nucleophile adducts,N-nitroso-N-substituted hydroxylamines,1,3-(nitrooxymethyl)phenyl-2-hydroxybenzoate, etc. , and/or anycombination of these and/or other compounds.

Besides L-arginine and L-arginine hydrochloride, other non-limitingexamples of nitric oxide donors include D,L-arginine, D-arginine, oralkyl (e.g., ethyl, methyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, etc.) esters of L-arginine and/or D-arginine (e.g., a methylester, an ethyl ester, a propyl ester, a butyl ester, etc.) and/or saltsthereof, as well as other derivatives of arginine and other nitric oxidedonors. For instance, non-limiting examples of pharmaceuticallyacceptable salts include hydrochloride, glutamate, butyrate, orglycolate (e.g., resulting in L-arginine glutamate, L-arginine butyrate,L-arginine glycolate, D-arginine hydrochloride, D-arginine glutamate,etc.). Still other examples of nitric oxide donors includeL-arginine-based compounds such as, but not limited to, L-homoarginine,N-hydroxy-L-arginine, nitrosylated L-arginine, nitrosylated L-arginine,nitrosylated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine,citrulline, ornithine, linsidomine, nipride, glutamine, etc., and saltsthereof (e.g., hydrochloride, glutamate, butyrate, glycolate, etc.),and/or any combination of these and/or other compounds. Still othernon-limiting examples of nitric oxide donors include S-nitrosothiols,nitrites, 2-hydroxy-2-nitrosohydrazines, or substrates of various formsof nitric oxide synthase. In some cases, the nitric oxide donor may be acompound that stimulates endogenous production of nitric oxide in vivo.Examples of such compounds include, but are not limited to, L-arginine,substrates of various forms of nitric oxide synthase, certain cytokines,adenosine, bradykinin, calreticulin, bisacodyl, phenolphthalein,OH-arginine, or endothelein, and/or any combination of these and/orother compounds.

Accordingly, it should be understood that, in any of the embodimentsdescribed herein that describe L-arginine and/or L-argininehydrochloride, other nitric oxide donors may also be used instead, or incombination with, L-arginine and/or L-arginine hydrochloride, in otherembodiments of the invention.

In some cases, the concentration of the nitric oxide donor within thecomposition may be tailored to have a duration of effective treatment ofat least about 3 hours, at least about 5 hours, or at least about 8hours or more in certain instances. The duration may also be controlled,for instance, by controlling the concentration of a penetrating agentused in conjunction with the nitric oxide donor. Penetration agents arediscussed in detail herein. The actual concentration for a particularapplication can be determined by those of ordinary skill in the artusing no more than routine experimentation, for example, by measuringthe amount of transport of the nitric oxide donor as a function ofconcentration in vitro across cadaver skin or suitable animal models,skin grafts, synthetic model membranes, human models, or the like.

As a particular non-limiting example, in certain embodiments, nitricoxide is provided using L-arginine, for example, at a concentration ofat least about 0.5% by weight (wt % or w/v) of L-arginine (optionallywith one or more penetrating agents as discussed herein, for example, apenetrating agent able to create a hostile biophysical environment), atleast about 0.75 wt %, at least about 1 wt %, at least about 2 wt %, atleast about 3 wt %, at least about 5 wt %, at least about 7 wt %, atleast about 10 wt %, or at least about 15 wt %. The L-arginine may bepresent in a suitable delivery vehicle, such as a cream or a lotion.L-arginine may be particularly useful in some cases due to its lowtoxicity, its high solubility, and/or its low cost. Other examples ofnitric oxide donors are discussed in International Patent ApplicationNo. PCT/US2005/005726, filed Feb. 23, 2005, entitled “Topical Deliveryof a Nitric Oxide Donor to Improve Body and Skin Appearance,” by E. T.Fossel, published as WO 2005/081964 on Sep. 9, 2005, incorporated hereinby reference.

Without wishing to be bound to any theory, it is generally believed thatthe flow of the pharmaceutical agent across the skin may slow as itbuilds up within the tissue. Fick's first law of diffusion suggests thatwhen the concentration inside becomes substantially equal to thatoutside, passive flow stops. The increased local blood flow may preventor at least decrease the stoppage of the flow of the pharmaceuticalagent. Thus, when the composition is applied to the skin, thepharmaceutical agent exits the vehicle into the tissue more readily, asthe pharmaceutical agent is dispersed by flow and does not build up inconcentration in the tissue. Thus, in certain embodiments,pharmaceutical agents may be introduced into the skin, for example,ibuprofen and/or an ibuprofen salt.

A hostile biophysical environment of the invention can comprise, invarious embodiments, high ionic strength, a high concentration ofosmotic agents such as ureas, sugars, or carbohydrates, a high pHenvironment (e.g., greater than about 9, greater than about 10, greaterthan about 11, greater than about 12, or greater than about 13), a lowpH environment (less than about 5, less than about 4, less than about 3or less than about 2), highly hydrophobic components, or highlyhydrophilic components or other substances that cause an increase in thechemical potential and/or free energy of the pharmaceutical agent, orany combination of two or more of these and/or other compounds. Ahydrophobic component may, in some embodiments, have an octanol-waterpartition coefficient of at least about 100, at least about 1000, atleast about 10⁴, at least about 10⁵, or more in some cases. Similarly, ahydrophilic component may have an octanol-water partition coefficient ofless than about 0.01, less than about 10⁻³, less than about 10⁻⁴, orless than about 10⁻⁵ in some cases.

In some cases, the composition defines the biophysical hostileenvironment. In other cases, a pharmaceutical agent may be packaged insuch a way that it is carried into tissue and/or its charge isneutralized by derivitization and/or by forming a neutral salt. Examplesof biophysically hostile environments include, but are not limited to,high ionic strength environments (e.g., by the addition of ureas,sugars, carbohydrates, and/or ionic salts such as lithium chloride,sodium chloride, potassium chloride, calcium chloride, magnesiumchloride, choline chloride, sodium fluoride, lithium bromide, etc.), aswell as combinations of these and/or other agents, for instance at highionic strengths (for example, greater than about 0.25 M, greater thanabout 1 M, greater than about 2 M, greater than about 3 M, greater thanabout 5 M, greater than about 10 M, greater than about 15 M, greaterthan about 20 M, greater than about 25 M, etc., or in some cases,between about 0.25 M and about 15 M, between about 5 M and about 15 M,between about 10 M and about 15 M, etc.); high or low pH environments(e.g., by adding pharmaceutically acceptable acids or bases, forexample, such that the pH is between about 3 and about 7, between about3 and about 6, between about 3 and about 5, between about 7 and about11, between about 8 and about 11, between about 9 and about 11, etc.);or highly hydrophobic environments (e.g., by decreasing water contentand increasing lipid, oil and/or wax content of the environment). Insome embodiments, the ionic strength is any amount greater than twotimes the physiological ionic strength of blood.

Other highly charged molecules such as polylysine, polyglutamine,polyaspartate, etc., or copolymers of such highly charged amino acidsmay also be used in certain embodiments to create the hostilebiophysical environment. Non-limiting examples of delivery vehicleswhich would be carried into tissue includes liposomes or emulsions ofcollagen, collagen peptides or other components of skin or basementmembrane. Non-limiting examples of neutralization of charge includedelivery of the pharmaceutical agent in the form or an ester or saltwhich is electronically neutral. In some embodiments, the hostilebiophysical environment may include any two or more of these conditions.For instance, the hostile biophysical environment may include high ionicstrength and a high pH or a low pH, a highly hydrophobic environment anda high pH or a low pH, a highly hydrophobic environment that includesliposomes, or the like.

A hostile biophysical environment may also be created in someembodiments by placing a pharmaceutical agent that is relatively highlycharged into a hydrophobic, oily environment such as in an oil-basedcream or lotion containing little or no water. Absorption may further beaided by combining the use of hostile biophysical environments with theuse of penetrating agents, as further described herein.

In one set of embodiments, the composition may be present as anemulsion. As known by those of ordinary skill in the art, an emulsiontypically includes a first phase (e.g., a discontinuous phase) containedwithin a second fluid phase (e.g., a continuous phase). Thepharmacological agent (e.g., ibuprofen) may be present in either or bothphases. In addition, other materials such as those described herein maybe present in the same phase as the pharmacological agent. For instance,when present, the nitric oxide donor, the stabilization polymer,propylene glycol, and/or the polysorbate surfactant may all be presentin the same phase as the pharmacological agent, e.g., in thediscontinuous phase and/or in the continuous phase.

Another aspect of the present invention is generally directed tocompositions for topical delivery having, by weight, at least about 50%,at least about 70%, at least about 80%, at least about 85%, at leastabout 90%, at least about 95%, or substantially all of the compositioncomprising water, at least one chloride salt, a nitric oxide donor, astabilization polymer, propylene glycol, a polysorbate surfactant, andibuprofen and/or an ibuprofen salt. The composition may also includeother components, for instance, glyceryl stearate, cetyl alcohol,squalane, isopropyl myristate, and/or oleic acid, which may form part orall of the balance of the composition. Examples of these and/or othercomponents are described herein.

Water may be present at any suitable concentration, for instance,present at a concentration of at least about 20%, at least about 25%, atleast about 30%, at least about 35%, at least about 40%, at least about45%, or at least about 50% by weight of the composition. In certainembodiments, the water is present at a concentration of about 40.9% byweight of the composition.

Non-limiting examples of chloride salts include sodium, potassiumchloride, calcium chloride, magnesium chloride, choline chloride, andthe like. In some cases, more than one chloride salt may be present, forexample, sodium chloride and potassium chloride. The chloride salt(s)may be present in any suitable concentration, and in some cases, thechloride salt(s) may create a hostile biophysical environment. Forinstance, the chloride salt(s) may be present at a concentration of atleast about 1%, at least about 2%, at least about 3%, at least about 4%,at least about 5%, at least about 6%, at least about 7%, at least about7.5%, at least about 8%, at least about 9%, at least about 10%, at leastabout 12%, at least about 15%, at least about 17%, or at least about 20%by weight of the composition.

As a non-limiting example, in one set of embodiments, the compositionmay consist essentially of water, sodium chloride, a nitric oxide donor,glyceryl stearate, cetyl alcohol, potassium chloride, squalane, astabilization polymer, isopropyl myristate, oleic acid, propyleneglycol, a polysorbate surfactant, and ibuprofen and/or an ibuprofensalt.

As specific non-limiting examples, in some cases, the glyceryl stearateis present at a concentration of about 7% by weight of the composition.In certain cases, the cetyl alcohol is present at a concentration ofabout 7% by weight of the composition. In one set of embodiments,squalene is present at a concentration of about 4% by weight of thecomposition. In some instances, potassium chloride is present at aconcentration of about 5% by weight of the composition. In one set ofembodiments, isopropyl myristate is present at a concentration of about1% by weight of the composition. In some cases, oleic acid is present ata concentration of about 1% by weight of the composition.

In some embodiments, the present invention is directed to a compositioncomprising each of the following compounds at concentrations of no morethan ±20% of the stated concentrations: water at a concentration ofabout 40.9% weight, sodium chloride at a concentration of about 10%weight, a nitric oxide donor at a concentration of about 7.5% weight,glyceryl stearate at a concentration of about 7% weight, cetyl alcoholat a concentration of about 7% weight, potassium chloride at aconcentration of about 5% weight, squalane at a concentration of about4% weight, a stabilization polymer at a concentration of about 0.8%weight; isopropyl myristate at a concentration of about 1% weight, oleicacid at a concentration of about 1% weight, propylene glycol at aconcentration of about 5% weight, a polysorbate surfactant at aconcentration of about 2% by weight; and ibuprofen and/or an ibuprofensalt at a concentration of about 7.5% weight.

In some aspects of the invention, a composition of the invention isadministered to a subject using a delivery vehicle such as a cream, gel,liquid, lotion, spray, aerosol, or transdermal patch. In one set ofembodiments, a composition of the invention may be applied orimpregnated in a bandage or a patch applied to the skin of a subject. A“subject,” as used herein, means a human or non-human animal. Examplesof subjects include, but are not limited to, a mammal such as a dog, acat, a horse, a donkey, a rabbit, a cow, a pig, a sheep, a goat, a rat(e.g., Rattus Norvegicus), a mouse (e.g., Mus musculus), a guinea pig, ahamster, a primate (e.g., a monkey, a chimpanzee, a baboon, an ape, agorilla, etc.), or the like. Such delivery vehicles may be applied tothe skin of a subject, such as a human subject. Examples of deliveryvehicles are discussed herein. The delivery vehicle may promote transferinto the skin of an effective concentration of the nitric oxide donorand/or the pharmaceutical agent, directly or indirectly. For instance,the delivery vehicle may include one or more penetrating agents, asfurther described herein. Those of ordinary skill in the art will knowof systems and techniques for incorporating a nitric oxide donor and/ora pharmaceutical agent within delivery vehicles such as a cream, gel,liquid, lotion, spray, aerosol, or transdermal patch. In some cases, theconcentration of the nitric oxide donor, and/or a pharmaceutical agentin the delivery vehicle can be reduced with the inclusion of a greateramount or concentration of penetrating agent, or increased to lengthenthe beneficial effect. In one set of embodiments, the nitric oxide donorand/or the pharmaceutical agent may be used in conjunction with anadjunct, such as theophylline (for example, at 10% weight by volume).

Other materials may be present within the delivery vehicle, for example,buffers, preservatives, surfactants, etc. For instance, the cream mayinclude one or more of water, mineral oil, glyceryl stereate, squalene,propylene glycol stearate, wheat germ oil, glyceryl stearate, isopropylmyristate, steryl stearate, polysorbate 60, propylene glycol, oleicacid, tocopherol acetate, collagen, sorbitan stearate, vitamin A and D,triethanolamine, methylparaben, aloe vera extract, imidazolidinyl urea,propylparaben, PND, and/or BHA.

As specific non-limiting examples, a cream may have one or more of(w/v): water (20-80%), white oil (3-18%), glyceryl stearate (0.25-12%),squalene (0.25-12%), cetyl alcohol (0.1-11%), propylene glycol stearate(0.1-11%), wheat germ oil (0.1-6%), polysorbate 60 (0.1-5%), propyleneglycol (0.05-5%), collagen (0.05-5%), sorbitan stearate (0.05-5%),vitamin A (0.02-4%), vitamin D (0.02-4%), vitamin E (0.02-4%),triethanolamine (0.01-4%), methylparaben (0.01-4%), aloe vera extract(0.01-4%), imidazolidinyl urea (0.01-4%), propylparaben (0.01-4%), BHA(0.01-4%), L-arginine hydrochloride (0.25-25%), sodium chloride(0.25-25%), magnesium chloride (0.25-25%), and/or choline chloride(0.25-25%). The percentages of each compound can vary (or the compoundmay be absent in some cases), for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%,8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, etc.

In another embodiment, the cream may include a pharmaceutical agent,such as ibuprofen, and one or more of the following, in any suitableamount: water (e.g., 20-80%), L-arginine hydrochloride (e.g., 0-25%),sodium chloride (e.g., 0-25%), potassium chloride (e.g., 0-25%), glyerylsteareate (e.g., 0-15%), cetyl alcohol (e.g., 0-15%), squalene (e.g.,0-15%), isopropyl mysterate (e.g., 0-15%), oleic acid (e.g., 0-15%),Tween 20 (e.g., 0-10%), and/or butanediol (e.g., 0-10%). The percentagesof each compound can vary (or the compound may be absent in some cases),for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%,14%, 15%, 20%, etc.

In some embodiments, the cream may include a pharmaceutical agent, andone or more ionic salts at a concentration at least sufficient toproduce a hostile biophysical environment with respect to thepharmaceutical agent. For example, the cream may include one or more of(w/v): a charged and/or hydrogen bonding entity (0.001-30%), cholinechloride (1-30%), sodium chloride (2-30%), and/or magnesium chloride(1-20% w/v). In another example, the cream may include one or more of(w/v): L-arginine hydrochloride (2.5-25%), choline chloride (10-30%),sodium chloride (5-20%), and/or magnesium chloride (5-20%). In stillanother example, the cream may include one or more of (w/v): creatine(0.001-30%), inosine (0.001-30%), choline chloride (1-30%), sodiumchloride (2-30%), magnesium chloride (1-20%), L-arginine (0.1-25%),and/or theophylline (0.1-20%). In some cases, the cream may also containL-arginine hydrochloride (0-12.5% w/v) and/or theophylline (0-10% w/v).The percentages of each compound can vary (or the compound may be absentin some cases), for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%,11%, 12%, 13%, 14%, 15%, 20%, etc. In these examples, choline chloride,sodium chloride, and/or magnesium chloride can be used to provide a highionic strength environment.

While ibuprofen and/or an ibuprofen salt is described herein, it shouldbe understood that this is by way of example only, and in otherembodiments, other pharmaceutical agents may be used instead of, or inaddition to, ibuprofen and/or an ibuprofen salt. Non-limiting examplesof pharmaceutical agents include small molecules (e.g., having amolecular weight of less than about 2,000 Da, less than about 1,500 Da,or less than about 1,000 Da), peptides (e.g., having less than about 10,less than about 15, less than about 20, or less than about 25 aminoacids), proteins (typically larger than peptides), hormones, vitamins,nucleic acids, or the like. Additional examples of suitablepharmaceutical agents for use with the present invention include, butare not limited to, NSAIDs (nonsteroidal anti-inflammatory drugs) suchas acetylsalicylic acid, naproxen, celecoxib, refecoxib, etc.;pharmaceutical agents with narcotic action such as morphine, codine,propoxyphene, oxycodone, hydrocodon, or other similar narcotics;pharmaceutical agents for erectile or sexual dysfunction such asyohimbie, alprostadil, sildenafil, cialis, uprima, vardenaifl, or thelike; pharmaceutical agents for migraine such as dihydroergotamine andits salts, ergotamine and its salts, surnatripan and its salts,rizatriptan and its salts, zolmitriptan and its salts, etc.;pharmaceutical agents for hair treatment such as finasteride,eflornithine, minoxidil, or the like; or other pharmaceutical agentssuch as niacin, lidocaine, benzocaine, naproxen, etc. Additionalexamples include muscle improving agents, for example, creatine orcreatine precursors (e.g., creatine phosphate), arginine and/or othernitric oxide donors, and/or ATP precursors such as, inosine, adenosine,inosine, adenine, hypoxanthine, ribose, phosphate (e.g., monosodiumphosphate), etc., and/or anabolic steroid agents, such as androstene,DHEA, androstenediol, androstenedione, or the like. Another example isephedra or its components, such as ephedrine and pseudoephedrine. Yetanother example are chemotherapeutic agents or agents for treatingcancer and/or viral infections, for example, but not limited totamoxifen (e.g., for breast cancer treatment), cis-platin, carboplatinand related molecules, cyclophosphamide and related molecules, vincaalkaloids, epipodophyllotoxins including taxol, acyclovir, or the like.For example, the cancer and/or viral infections may be skin cancer,breast cancer, penile cancer, testicular cancer, or other localizedcancers, or viral infections, such as herpes.

In certain aspects of the invention, a pharmaceutical agent may becombined with a penetrating agent, i.e., an agent that increasestransport of the pharmaceutical agent into the skin, relative totransport in the absence of the penetrating agent. In some embodiments,the penetrating agent may define and/or be combined with a hostilebiophysical environment. Examples of penetrating agents includeoleoresin capsicum or its constituents, or certain molecules containingheterocyclic rings to which are attached hydrocarbon chains.

Non-limiting examples of penetrating agents include, but are not limitedto, cationic, anionic, or nonionic surfactants (e.g., sodium dodecylsulfate, polyoxamers, etc.); fatty acids and alcohols (e.g., ethanol,oleic acid, lauric acid, liposomes, etc.); anticholinergic agents (e.g.,benzilonium bromide, oxyphenonium bromide); alkanones (e.g., n-heptane);amides (e.g., urea, N,N-dimethyl-m-toluamide); fatty acid esters (e.g.,n-butyrate); organic acids (e.g., citric acid); polyols (e.g., ethyleneglycol, glycerol); sulfoxides (e.g., dimethylsulfoxide); terpenes (e.g.,cyclohexene); ureas; sugars; carbohydrates or other agents. In certainembodiments, the penetrating agent includes a salt, e.g., as describedherein.

Thus, another aspect of the invention provides for the delivery ofpharmaceutical agents (e.g., drugs, biological compounds, etc.) into thebody, and such treatments may be systemic or localized, e.g., directedto a specific location of the body, such as the head, one or morespecific muscles, the genitals, etc., depending on the specificapplication.

In one set of embodiments, pharmaceutical agents are introduced to aidin treatment of medical conditions or diseases, and the symptomsassociated thereof. In some embodiments, the invention provides for thetreatment of medical conditions or diseases and/or ailments usingpharmaceutical agents (for example, to treat a subject diagnosed with amedical condition or disease), and in some cases, the invention providesfor the delivery of a minimum amount of pharmaceutical agents to provideeffective levels of medication to an effected area topically whilelimiting side effects. In some cases, the effective dosage of thepharmaceutical agent may be lower than the effective dosage of thepharmaceutical agent when taken orally. Other embodiments of theinvention provide methods for treating pain, for example, pain frommigraine, pain from arthritis, other headaches, joint pain, muscle painand other types of pain. Accordingly, in some embodiments, a compositionmay be topically applied to a specific location of the body, e.g., to asite of pain. Also, in certain cases, a composition as described hereinmay be used in the preparation of a medicament for treatment of pain, orother diseases or conditions as discussed herein.

In another aspect, the present invention is directed to a kit includingone or more of the compositions discussed herein. A “kit,” as usedherein, typically defines a package or an assembly including one or moreof the compositions of the invention, and/or other compositionsassociated with the invention, for example, as described herein. Each ofthe compositions of the kit may be provided in liquid form (e.g., insolution), or in solid form (e.g., a dried powder). In certain cases,some of the compositions may be constitutable or otherwise processable(e.g., to an active form), for example, by the addition of a suitablesolvent or other species, which may or may not be provided with the kit.Examples of other compositions or components associated with theinvention include, but are not limited to, solvents, surfactants,diluents, salts, buffers, emulsifiers, chelating agents, fillers,antioxidants, binding agents, bulking agents, preservatives, dryingagents, antimicrobials, needles, syringes, packaging materials, tubes,bottles, flasks, beakers, dishes, frits, filters, rings, clamps, wraps,patches, containers, and the like, for example, for using,administering, modifying, assembling, storing, packaging, preparing,mixing, diluting, and/or preserving the compositions components for aparticular use, for example, to a sample and/or a subject.

A kit of the invention may, in some cases, include instructions in anyform that are provided in connection with the compositions of theinvention in such a manner that one of ordinary skill in the art wouldrecognize that the instructions are to be associated with thecompositions of the invention. For instance, the instructions mayinclude instructions for the use, modification, mixing, diluting,preserving, administering, assembly, storage, packaging, and/orpreparation of the compositions and/or other compositions associatedwith the kit. In some cases, the instructions may also includeinstructions for the delivery and/or administration of the compositions,for example, for a particular use, e.g., to a sample and/or a subject.The instructions may be provided in any form recognizable by one ofordinary skill in the art as a suitable vehicle for containing suchinstructions, for example, written or published, verbal, audible (e.g.,telephonic), digital, optical, visual (e.g., videotape, DVD, etc.) orelectronic communications (including Internet or web-basedcommunications), provided in any manner.

In some embodiments, the present invention is directed to methods ofpromoting one or more embodiments of the invention as discussed herein,for example, methods of promoting the making or use of compositions suchas those discussed above, methods of promoting kits as discussed above,or the like. As used herein, “promoted” includes all methods of doingbusiness including, but not limited to, methods of selling, advertising,assigning, licensing, contracting, instructing, educating, researching,importing, exporting, negotiating, financing, loaning, trading, vending,reselling, distributing, repairing, replacing, insuring, suing,patenting, or the like that are associated with the systems, devices,apparatuses, articles, methods, compositions, kits, etc. of theinvention as discussed herein. Methods of promotion can be performed byany party including, but not limited to, personal parties, businesses(public or private), partnerships, corporations, trusts, contractual orsub-contractual agencies, educational institutions such as colleges anduniversities, research institutions, hospitals or other clinicalinstitutions, governmental agencies, etc. Promotional activities mayinclude communications of any form (e.g., written, oral, and/orelectronic communications, such as, but not limited to, e-mail,telephonic, Internet, Web-based, etc.) that are clearly associated withthe invention.

In one set of embodiments, the method of promotion may involve one ormore instructions. As used herein, “instructions” can define a componentof instructional utility (e.g., directions, guides, warnings, labels,notes, FAQs or “frequently asked questions,” etc.), and typicallyinvolve written instructions on or associated with the invention and/orwith the packaging of the invention. Instructions can also includeinstructional communications in any form (e.g., oral, electronic,audible, digital, optical, visual, etc.), provided in any manner suchthat a user will clearly recognize that the instructions are to beassociated with the invention, e.g., as discussed herein.

The following documents are incorporated herein by reference:International Patent Application No. PCT/US98/19429, filed Sep. 17,1998, entitled “A Delivery of Arginine to Cause Beneficial Effects,” byE. Fossel, published as WO 99/13717 on Mar. 25, 1999; InternationalPatent Application No. PCT/US2005/005726, filed Feb. 23, 2005, entitled“Topical Delivery of a Nitric Oxide Donor to Improve Body and SkinAppearance,” by E. Fossel, et al., published as WO 2005/081964 on Sep.9, 2005; International Patent Application No. PCT/US2005/013228, filedApr. 19, 2005, entitled “Transdermal Delivery of Beneficial SubstancesEffected by a Hostile Biophysical Environment,” by E. Fossel, publishedas WO 2005/102282 on Nov. 3, 2005; and International Patent ApplicationNo. PCT/US2005/013230, filed Apr. 19, 2005, entitled “Beneficial Effectsof Increasing Local Blood Flow,” by E. Fossel, published as WO2005/102307 on Nov. 3, 2005.

Also incorporated by reference herein are U.S. patent application Ser.No. 08/932,227, filed Sep. 17, 1997, entitled “Topical Delivery ofArginine of Cause Beneficial Effects,” by E. T. Fossel, published as2002/0041903 on Apr. 11, 2002; U.S. patent application Ser. No.10/201,635, filed Jul. 22, 2002, entitled “Topical Delivery ofL-Arginine to Cause Beneficial Effects,” by E. T. Fossel, published as2003/0028169 on Feb. 6, 2003; U.S. patent application Ser. No.10/213,286, filed Aug. 5, 2002, entitled “Topical and Oral Arginine toCause Beneficial Effects,” by E. T. Fossel, published as 2003/0018076 onJan. 23, 2003; U.S. Pat. No. 5,895,658, issued Apr. 20, 1999, entitled“Topical Delivery of L-Arginine to Cause Tissue Warming,” by E. T.Fossel; U.S. Pat. No. 5,922,332, issued Jul. 13, 1999, entitled “TopicalDelivery of Arginine to Overcome Pain,” by E. T. Fossel; U.S. Pat. No.6,207,713, issued Mar. 27, 2001, entitled “Topical and Oral Delivery ofArginine to Cause Beneficial Effects,” by E. T. Fossel; and U.S. Pat.No. 6,458,841, issued Oct. 1, 2002, entitled “Topical and Oral Deliveryof Arginine to Cause Beneficial Effects,” by E. T. Fossel.

The following examples are intended to illustrate certain embodiments ofthe present invention, but do not exemplify the full scope of theinvention.

EXAMPLE 1

This example illustrates one method of preparing a transdermal formulaof the invention including ibuprofen. The final composition is shown inTable 1. Of course, those of ordinary skill in the art will understandthat percentages other than the ones listed below are also possible,according to other embodiments of the invention.

TABLE 1 Ingredient % w/w Water 40.9 Sodium Chloride 10.0 L-ArginineHydrochloride 7.5 Ibuprofen (sodium salt) 7.5 Glyceryl Stearate (SE) 7.0Cetyl Alcohol 7.0 Potassium Chloride 5.0 Squalane 4.0 Xanthan Gum 0.8Isopropyl Myristate 1.0 Oleic Acid 1.0 Propylene Glycol 5.0Polysorbate-20 2.0

To prepare the formulation in this example, sodium chloride, potassiumchloride, L-arginine and ibuprofen were mixed in water, then heated to74° C. with rapid mixing. In a separate container, the remainingingredients were mixed together and heated to 74° C. The otheringredients were then added to the water phase at 74° C. with rapidmixing. The mixture was then cooled to room temperature with continuedmixing. At this point, an emulsion formed with a relatively thinconsistency. The emulsion was then homogenized at high speed at roomtemperature to thicken the consistency.

While several embodiments of the present invention have been describedand illustrated herein, those of ordinary skill in the art will readilyenvision a variety of other means and/or structures for performing thefunctions and/or obtaining the results and/or one or more of theadvantages described herein, and each of such variations and/ormodifications is deemed to be within the scope of the present invention.More generally, those skilled in the art will readily appreciate thatall parameters, dimensions, materials, and configurations describedherein are meant to be exemplary and that the actual parameters,dimensions, materials, and/or configurations will depend upon thespecific application or applications for which the teachings of thepresent invention is/are used. Those skilled in the art will recognize,or be able to ascertain using no more than routine experimentation, manyequivalents to the specific embodiments of the invention describedherein. It is, therefore, to be understood that the foregoingembodiments are presented by way of example only and that, within thescope of the appended claims and equivalents thereto, the invention maybe practiced otherwise than as specifically described and claimed. Thepresent invention is directed to each individual feature, system,article, material, kit, and/or method described herein. In addition, anycombination of two or more such features, systems, articles, materials,kits, and/or methods, if such features, systems, articles, materials,kits, and/or methods are not mutually inconsistent, is included withinthe scope of the present invention.

All definitions, as defined and used herein, should be understood tocontrol over dictionary definitions, definitions in documentsincorporated by reference, and/or ordinary meanings of the definedterms.

The indefinite articles “a” and “an,” as used herein in thespecification and in the claims, unless clearly indicated to thecontrary, should be understood to mean “at least one.”

The phrase “and/or,” as used herein in the specification and in theclaims, should be understood to mean “either or both” of the elements soconjoined, i.e., elements that are conjunctively present in some casesand disjunctively present in other cases. Multiple elements listed with“and/or” should be construed in the same fashion, i.e., “one or more” ofthe elements so conjoined. Other elements may optionally be presentother than the elements specifically identified by the “and/or” clause,whether related or unrelated to those elements specifically identified.Thus, as a non-limiting example, a reference to “A and/or B”, when usedin conjunction with open-ended language such as “comprising” can refer,in one embodiment, to A only (optionally including elements other thanB); in another embodiment, to B only (optionally including elementsother than A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc.

As used herein in the specification and in the claims, “or” should beunderstood to have the same meaning as “and/or” as defined above. Forexample, when separating items in a list, “or” or “and/or” shall beinterpreted as being inclusive, i.e., the inclusion of at least one, butalso including more than one, of a number or list of elements, and,optionally, additional unlisted items. Only terms clearly indicated tothe contrary, such as “only one of” or “exactly one of,” or, when usedin the claims, “consisting of,” will refer to the inclusion of exactlyone element of a number or list of elements. In general, the term “or”as used herein shall only be interpreted as indicating exclusivealternatives (i.e. “one or the other but not both”) when preceded byterms of exclusivity, such as “either,” “one of,” “only one of,” or“exactly one of.” “Consisting essentially of,” when used in the claims,shall have its ordinary meaning as used in the field of patent law.

As used herein in the specification and in the claims, the phrase “atleast one,” in reference to a list of one or more elements, should beunderstood to mean at least one element selected from any one or more ofthe elements in the list of elements, but not necessarily including atleast one of each and every element specifically listed within the listof elements and not excluding any combinations of elements in the listof elements. This definition also allows that elements may optionally bepresent other than the elements specifically identified within the listof elements to which the phrase “at least one” refers, whether relatedor unrelated to those elements specifically identified. Thus, as anon-limiting example, “at least one of A and B” (or, equivalently, “atleast one of A or B,” or, equivalently “at least one of A and/or B”) canrefer, in one embodiment, to at least one, optionally including morethan one, A, with no B present (and optionally including elements otherthan B); in another embodiment, to at least one, optionally includingmore than one, B, with no A present (and optionally including elementsother than A); in yet another embodiment, to at least one, optionallyincluding more than one, A, and at least one, optionally including morethan one, B (and optionally including other elements); etc.

It should also be understood that, unless clearly indicated to thecontrary, in any methods claimed herein that include more than one stepor act, the order of the steps or acts of the method is not necessarilylimited to the order in which the steps or acts of the method arerecited.

In the claims, as well as in the specification above, all transitionalphrases such as “comprising,” “including,” “carrying,” “having,”“containing,” “involving,” “holding,” “composed of,” and the like are tobe understood to be open-ended, i.e., to mean including but not limitedto. Only the transitional phrases “consisting of” and “consistingessentially of” shall be closed or semi-closed transitional phrases,respectively, as set forth in the United States Patent Office Manual ofPatent Examining Procedures, Section 2111.03.

What is claimed is: 1-112. (canceled)
 113. A composition for topicaldelivery to the skin of a subject, the composition comprising: an ionicstrength of at least about 0.25 M; a stabilization polymer comprisingxanthan gum; propylene glycol; a polysorbate surfactant; and ibuprofenand/or an ibuprofen salt.
 114. The composition of claim 113, wherein thecomposition comprises an ionic salt.
 115. The composition of claim 113,wherein the composition comprises sodium chloride.
 116. The compositionof claim 113, wherein the sodium chloride is present at at least about5% by weight of the composition.
 117. The composition of claim 113,wherein the composition comprises one or more salts selected from thegroup consisting of choline chloride, magnesium chloride, lithiumchloride, and calcium chloride.
 118. The composition of claim 113,wherein the composition comprises citric acid.
 119. The composition ofclaim 113, wherein the composition is stable when exposed to atemperature of 40° C. for at least about 4 weeks.
 120. The compositionof claim 113, wherein the composition is a cream.
 121. The compositionof claim 113, wherein the composition is a gel.
 122. The composition ofclaim 113, wherein the composition is a lotion.
 123. The composition ofclaim 113, wherein the composition has an ionic strength of at leastabout 1 M.
 124. The composition of claim 113, wherein the compositionhas a pH of between about 5 and about
 9. 125. The composition of claim113, wherein the composition is capable of driving the ibuprofen and/oran ibuprofen salt through stratum corneum.
 126. The composition of claim113, wherein the stabilization polymer is present at at least about 0.5%by weight of the composition.
 127. The composition of claim 113, whereinthe propylene glycol is present at at least about 1% by weight of thecomposition.
 128. The composition of claim 113, wherein the polysorbatesurfactant is present at at least about 1% by weight of the composition.129. The composition of claim 113, wherein the ibuprofen and/or theibuprofen salt is present at at least about 0.1% by weight of thecomposition.
 130. A method of topically treating or reducinginflammation or pain in a subject, comprising applying the compositionof claim 113 to a site of inflammation or pain of the subject.
 131. Themethod of claim 130, wherein the subject is a human.